FOXM1 confers to epithelial-mesenchymal transition, stemness and chemoresistance in epithelial ovarian carcinoma cells

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// Wen-Tai Chiu 1,2 , Yu-Fang Huang 3 , Huei-Yu Tsai 4 , Chien-Chin Chen 5,6 , Chang-Hwa Chang 2 , Soon-Cen Huang 7 , Keng-Fu Hsu 3,4 and Cheng-Yang Chou 3,4 1 Department of Biomedical Engineering, National Cheng Kung University, Tainan, Taiwan 2 Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan 3 Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan 4 Cancer Research Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan 5 Department of Pathology, Chia-Yi Christian Hospital, Chiayi, Taiwan 6 Department of Cosmetic Science, Chia Nan University of Pharmacy and Science, Tainan, Taiwan 7 Department of Obstetrics and Gynecology, Chi Mei Medical Center, Liouying Campus, Tainan, Taiwan Correspondence: Cheng-Yang Chou, email: // Keywords : ovarian cancer, FOXM1, β-CATENIN, chemoresistance, stemness Received : October 15, 2014 Accepted : December 09, 2014 Published : December 10, 2014 Abstract Chemoresistance to anti-cancer drugs substantially reduces survival in epithelial ovarian cancer. In this study, we showed that chemoresistance to cisplatin and paclitaxel induced the epithelial-mesenchymal transition (EMT) and a stem cell phenotype in ovarian cancer cells. Chemoresistance was associated with the downregulation of epithelial markers and the upregulation of mesenchymal markers, EMT-related transcription factors, and cancer stem cell markers, which enhanced invasion and sphere formation ability. Overexpression of FOXM1 increased cisplatin-resistance and sphere formation in cisplatin-sensitive and low FOXM1-expressing ovarian cancer cells. Conversely, depletion of FOXM1 via RNA interference reduced cisplatin resistance and sphere formation in cisplatin-resistant and high FOXM1-expressing cells. Overexpression of FOXM1 also increased the expression, nuclear accumulation, and activity of β-CATENIN in chemoresistant cells, whereas downregulation of FOXM1 suppressed these events. The combination of cisplatin and the FOXM1 inhibitor thiostrepton inhibited the expression of stem cell markers in chemoresistant cells and subcutaneous ovarian tumor growth in mouse xenografts. In an analysis of 106 ovarian cancer patients, high FOXM1 levels in tumors were associated with cancer progression and short progression-free intervals. Collectively, our findings highlight the importance of FOXM1 in chemoresistance and suggest that FOXM1 inhibitors may be useful for treatment of ovarian cancer.

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